The present invention relates to novel ester derivatives of glycosaminoglycanes (GAG) such as hyaluronic acid (HA) with derivatives of hydroxy-cinnamic acid, such as ferulic acid and caffeic acid.
HA is a GAG consisting of a repeating sequence of a disaccharide unit formed by glucuronic acid and N-acetyl-glucosamine.
HA carries out several biological functions, which span from the regulation of the water present in the tissues to the cellular motility and also has, in the derma, a function as a supporting scaffold by binding with other substances to form macromolecular complexes which provide compactness to the skin.
The hydroxy-cinnamic acid derivatives such as ferulic acid and caffeic acid are widely distributed within the seeds and the leaves of the vegetable world in a free form or covalently bonded with lignine or other biopolymers. Owing to the phenolic nucleous and to the extended conjugation of the side chain, they form phenoxy radicals, which are stabilised by resonance which generate their potent antioxidant and protective function in various inflammatory pathologies and in the protective property of cells exposed to ultraviolet radiations.
Hyaluronic acid is a moisturizing substance which, at the skin level, acts by retaining transepidermic water. It is however a highly hydrophilic molecule which penetrates with difficulty into the highly lipidic horny layer and it is moreover a substance which is subject to rapid degradation. One of the advantages of the compounds of the present invention is that the presence of hydroxy-cinnamic substituents of the modified polymer provides protection from enzymatic degradation operated by hyaluronidase which is present in the tissues; moreover, the esterification of HA with the hydroxy-cinnamic acid derivatives has allowed to obtain compounds with enhanced lipophilic properties, with respect to the native polimer and which can therefore be more easily bio-absorbed through the epidermis.
In view of its chemical, physical and biological properties, HA has been particularly studied and has been the subject of structural modifications and there are several publications and patents relating to new derivatives.
Several works were carried out on processes for reticulation of HA so as to obtain viscoelastic products to be used primarily for intra-articular administration in the arthrosis therapy, such as described, for instance, by EP 0 341 745, or to be used also as a post-surgical anti-adhesive, as described e.g. by U.S. Pat. No. 4,582,865.
Relatively lower is the number of patents or publications relating to esters obtained on the hydroxy groups of HA with organic acids.
Among these we can refer to U.S. Pat. No. 5,679,567, which describes the preparation of acetylated HA with different substitution degrees. WO2005/092929 and Inv. New Drugs (2004), 22 (3), 207-217, describe ester derivatives of HA with butyrric acid, which are endowed with anti-proliferative activity and which are therefore potentially useful for antitumoral use, whereas WO2008/081255 describes other ester derivatives of HA with butyrric acid, but with a high reticulation degree and which are to be used primarily as viscosity-elasticity enhancing agents for intra-articular administration. Other ester derivatives of HA are described by Picotti et al. in WO2009/080220, wherein HA is esterified with the lipoic acid to provide derivatives for dermocosmetic use or as a medical device for intra-articular treatment.
In our knowledge, up to now, there is no description of polysaccharide esters and more specifically of esters of HA with hydroxy-cinnamic acid derivatives, such as ferulic and caffeic acid for dermoprotective use as compounds having elasticity-enhancing, moisturising, softening activity or for use as medical devices with anti-reddening or soothing activity of the herythematous conditions induced by radiation or as viscosity-supplementing agents.